The present invention relates to the use of a thienylcyclohexylamine, by itself or in combination with other substances with a pharmaceutical activity, for the preparation of a medicament intended to limit or inhibit the effects due to neurotoxic products or those containing neurotoxin. The invention also relates to a product containing a thienylcyclohexylamine and at least one anticholinergic, anticonvulsive or cholinesterase reactivator, and a pharmaceutical composition containing it. This product is also particularly useful for its activity of limiting or inhibiting the effects due to neurotoxic products or those containing neurotoxin.
The family of neurotoxic products or those containing neurotoxin includes products such as the organophosphates which can be found, for example, in insecticides or pesticides for domestic or industrial use, but also poison gas for use in warfare, such as soman, sarin, tabun or VX. Among the existing therapies such as polymedication to combat intoxication by such compounds, none totally prevents the appearance of neuropathological after-effects.
A subject of the invention is the use of thienylcyclohexylamine corresponding to the formula 2-methyl-1-(1-piperidinyl)-1-(2-thienyl) cyclohexane, for the preparation of a medicament intended to limit or inhibit the effects due to neurotoxic products or those containing neurotoxin in primates and in particular in man. It can be used by itself or in combination with other substances with a pharmaceutical activity capable of limiting or inhibiting the effects due to neurotoxic products or those containing neurotoxin.
Thienylcyclohexylamine as defined above, is described in Patent EP 396734. Taking into account the existence of 2 asymmetric carbons, this thienylcyclohexylamime can be in substantially pure racemic, diastereoisomeric or enantiomeric form. The cis diastereoisomer (named gacyclidine) is the preferred compound.
The preparation of the diastereoisomers of 1-thienylcyclohexylamine consists of reacting the 2-bromothienyl-magnesium compound on 2-methylcyclo hexanone, and treating the 2-methyl-1-(2-thienyl) cyclohexanol thus obtained with NaN3 in order to obtain the corresponding azide, reducing this azide into the amine and finally treating with 1,5-halogenopentane. The cis and trans diastereoisomers are separated by preparative chromatography on silica gel, using a hexane/ether mixture (95/5 by volume): the first fraction, corresponding to the trans compound, crystallizes at 40-41xc2x0 C.; the second fraction, corresponding to the cis compound, crystallizes at 80-81xc2x0 C. The enantiomers can be obtained by using optically active acids such as di-O,Oxe2x80x2-4-toluoyltartaric acid.
A particular subject of the invention is the use of thienylcyclohexylamine as defined above, with at least one substance chosen from anticholinergic, anticonvulsive substances and substances which reactivate cholinesterases.
A particular subject of the invention is the use of thienylcyclohexylamine as defined above, with at least one anticholinergic substance, at least one anticonvulsive substance and at least one substance which reactivates cholinesterases.
The pharmacological terms used have the standard meaning known to a person skilled in the art. Therefore, among the anticholinergic substances, the following substances can be mentioned: atropine, scopolamine, atropine N-oxide, dihexyverine and tiemonium methylsulphate. Among the anticonvulsive substances, the following substances can for example be mentioned: phenobarbital, primidone, carbamazepine, ethosuximide, phenytoin, sodium valproate, progabide, gabapentin, vigabatrin, loprazolam, benzodiazepins such as clonazepaim, clobazam, diazepam and prodiazepam. Among the substances which reactivate cholinesterases, there can be mentioned pralidoxime, obidoxime, HI6.
A subject of the invention is also a use of thienylcyclohexylamine as defined above, characterized in that the thienylcyclohexylamine is combined with a reversible cholinesterase inhibitor intended to be administered before exposure to neurotoxic products or those containing neurotoxin. Among the reversible cholinesterase inhibitors, the following can be mentioned: pyridostigmine, physostigmine.
The thienylcyclohexylamine as defined above and the other susbtances as above defined are combined for simultaneous use, separate use or use spread over time.
A subject of the invention is also, as a medicament, a product containing thienylcyclohexylamine as defined above, combined with at least one substance with a pharmaceutical activity capable of limiting or inhibiting the effects due to neurotoxic products or those containing neurotoxin, as well as the pharmaceutical compositions containing it.
A more particular subject of the invention is, as a medicament, a product containing thienylcyclohexylamine as defined above, in substantially pure racemic, diastereoisomeric or enantiomeric form, combined with at least one substance chosen from anticholinergic, anticonvulsive substances and substances which reactivate cholinesterases. Preferably, the product as defined above, contains thienylcyclohexylamine as defined above, combined with at least one anticholinergic substance, one anticonvulsive substance and one substance which reactivates cholinesterases. A medicament corresponding to a combination product as defined above is for simultaneous use, separate use or use spread over time.
The invention also relates to a product containing thienylcyclohexylamine and at least one substance chosen from anticholinergic, anticonvulsive substances and substances which reactivate cholinesterases as a combination product for simultaneous use, separate use or use spread over time, to limit or inhibit the effects due to neurotoxic products or those containing neurotoxin.
A subject of the invention is also a product as defined above characterized in that in addition it contains a reversible cholinesterase inhibitor intended to be administered before exposure to neurotoxic products or those containing neurotoxin.
Thienylcyclohexylamine as defined above, can be administered at a dose comprised between 0.001 and 10 mg/kg, preferably between 0.01 and 1 mg/kg. The substances which are optionally combined with it such as anticholinergic, anticonvulsive substances, substances which reactivate cholinesterases or reversible cholinesterase inhibitors, known in pharmacology, are administered at doses usually recommended in their respective pharmacological fields.
Thienylcyclohexylamine as defined above as well as the pharmaceutically active substances with which it is optionally-combined, can be administered by standard administration routes such as oral, intramuscular, intraperitoneal, sub-cutaneous or intravenous. They can be administered simultaneously or separately, by identical or different administration routes. Preferably, thienylcyclohexylamine is administered by intravenous route and the pharmaceutically-active substances with which it is optionally combined such as the anticholinergic, anticonvulsive substances and the substances which reactivate cholinesterases, are administered by intramuscular or intravenous route. In the case where thienylcyclohexylamine is combined with at least one of the pharmaceutically active substances as defined above, the administration of thienylcyclohexylamine can be deferred with respect to the administration of these other substances.
When thienylcyclohexylamine is combined with a reversible cholinesterase inhibitor, it may be administrated from the moment of intoxication up to several hours after this intoxication. Preferably, this administration is carried out within two hours of the intoxication. More preferably, this administration can be carried out between 10 minutes and 45 minutes after intoxication.
When thienylcyclohexylamine is not combined with a reversible cholinesterase inhibitor, it may be administrated from the moment of intoxication up to 60 minutes after the intoxication and preferably up to 40 minutes after intoxication, and more preferably 30 minutes after intoxication.
The results shown hereafter in the experimental part, first and second series of experiments, illustrate the high effectiveness of the complementary administration of gacyclidine 10 to 45 minutes after intoxication and a pre-administration of a cholinesterase inhibitor.The results shown hereafter in the experimental part, third series of experiments, illustrate the high effectiveness of the complementary administration of cis-thienylcyclohexylamine 30 minutes after intoxication and without a pre-administration of a cholinesterase inhibitor.